title: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients.
abstract: OBJECTIVE
  To assess whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the toxicity of chemotherapy and alters delivered dose-intensity. To assess the feasibility of dose-intensification of chemotherapy in small-cell lung cancer (SCLC) and determine whether it has an impact on outcome.
  
  
  METHODS
  Patients with good- or intermediate-prognosis SCLC entered a prospective multicenter study that involved a 2 x 2 factorial design with randomization to six cycles of chemotherapy with ifosfamide 5 g/m2, carboplatin 300 mg/m2, etoposide 120 mg/m2 intravenously (I.V.) on days 1 and 2 and 240 mg/m2 orally on day 3, and vincristine 0.5 mg/m2 I.V. on day 15 (V-ICE) every 3 weeks (intensified arm) or every 4 weeks (standard arm). A second double-blind randomization to subcutaneous GM-CSF (250 microg/m2/d) or placebo for 14 days between chemotherapy cycles was made.
  
  
  RESULTS
  Three hundred patients were entered. Myelosuppression was the main toxicity, with no significant difference in the incidence or grade between treatment groups. The incidence of febrile neutropenia and bacteriologically confirmed sepsis was unaffected by chemotherapy schedule or use of GM-CSF. Twenty-six percent greater dose-intensity was delivered in the intensified arm, with a trend for greater dose-intensity for those who received GM-CSF. Eighty-three percent of patients achieved a response (51% complete response [CR] rate), with no significant difference in response rates between treatment groups. Survival was significantly increased in the intensified compared with the standard arm (P = .0014); median survival rates were 443 versus 351 days and 2-year survival rates were 33% versus 18%, respectively.
  
  
  CONCLUSIONS
  GM-CSF does not reduce the incidence of complications from myelosuppression of aggressive chemotherapy. Dose intensification of V-ICE to a 3-week schedule in SCLC is not associated with increased toxicity, but appears to improve survival significantly. Future studies should aim to deliver chemotherapy in maximal-tolerated dose-intensities.
authors.affiliation: Department of Oncology, Leicester Royal Infirmary, United Kingdom. william.steward@uni.romp.msmail.lri-tr.trent.nhs.uk
authors.forename: W P
authors.initials: WP
authors.lastname: Steward
authors.forename: J
authors.initials: J
authors.lastname: von Pawel
authors.forename: U
authors.initials: U
authors.lastname: Gatzemeier
authors.forename: P
authors.initials: P
authors.lastname: Woll
authors.forename: N
authors.initials: N
authors.lastname: Thatcher
authors.forename: G
authors.initials: G
authors.lastname: Koschel
authors.forename: L
authors.initials: L
authors.lastname: Clancy
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: R
authors.initials: R
authors.lastname: de Wit
authors.forename: W
authors.initials: W
authors.lastname: Pfeifer
authors.forename: J
authors.initials: J
authors.lastname: Fennelly
authors.forename: M
authors.initials: M
authors.lastname: von Eiff
authors.forename: J
authors.initials: J
authors.lastname: Frisch
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000401:mortality; D004311:Double-Blind Method; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015996:Survival Rate; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D014750:Vincristine; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016190:Carboplatin; D007069:Ifosfamide